This invention relates to novel 1,4-disubstituted benzo-fused cycloalkyl urea compounds of formula(I): 
wherein X, A, L, J, Q and Y of formula(I) are defined below. The compounds of the invention inhibit production of cytokines involved in inflammatory processes and are thus useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease. This invention also relates to processes for preparing these compounds and to pharmaceutical compositions comprising these compounds.
Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are important biological entities collectively referred to as proinflammatory cytokines. These, along with several other related molecules, mediate the inflammatory response associated with the immunological recognition of infectious agents. The inflammatory response plays an important role in limiting and controlling pathogenic infections.
Elevated levels of proinflammatory cytokines are also associated with a number of diseases of autoimmunity such as toxic shock syndrome, rheumatoid arthritis, osteoarthritis, diabetes and inflammatory bowel disease (Dinarello, C. A., et al., 1984, Rev. Infect. Disease 6:51). In these diseases, chronic elevation of inflammation exacerbates or causes much of the pathophysiology observed. For example, rheumatoid synovial tissue becomes invaded with inflammatory cells that result in destruction to cartilage and bone (Koch, A. E., et al., 1995, J. Invest. Med. 43: 28-38). Studies suggest that inflammatory changes mediated by cytokines may be involved in the pathogenesis of restenosis after percutaneous transluminal coronary angioplasty (PTCA) (Tashiro, H., et al., 2001 March, Coron Artery Dis 12(2): 107-13). An important and accepted therapeutic approach for potential drug intervention in these diseases is the reduction of proinflammatory cytokines such as TNF (also referred to in its secreted cell-free form as TNFxcex1) and IL-1xcex2. A number of anti-cytokine therapies are currently in clinical trials. Efficacy has been demonstrated with a monoclonal antibody directed against TNFxcex1 in a number of autoimmune diseases (Heath, P., xe2x80x9cCDP571: An Engineered Human IgG4 Anti-TNFxcex1 Antibodyxe2x80x9d IBC Meeting on Cytokine Antagonists, Philadelphia, Pa., Apr. 24-5, 1997). These include the treatment of rheumatoid arthritis, Crohn""s disease and ulcerative colitis (Rankin, E. C. C., et al., 1997, British J. Rheum. 35: 334-342 and Stack, W. A., et al., 1997, Lancet 349: 521-524). The monoclonal antibody is thought to function by binding to both soluble TNFxcex1 and to membrane bound TNF.
A soluble TNFxcex1 receptor has been engineered that interacts with TNFxcex1. The approach is similar to that described above for the monoclonal antibodies directed against TNFxcex1; both agents bind to soluble TNFxcex1, thus reducing its concentration. One version of this construct, called Enbrel (Immunex, Seattle, Wash.) recently demonstrated efficacy in a Phase III clinical trial for the treatment of rheumatoid arthritis (Brower et al., 1997, Nature Biotechnology 15: 1240). Another version of the TNFxcex1 receptor, Ro 45-2081 (Hoffman-LaRoche Inc., Nutley, N.J.) has demonstrated efficacy in various animal models of allergic lung inflammation and acute lung injury. Ro 45-2081 is a recombinant chimeric molecule constructed from the soluble 55 kDa human TNF receptor fused to the hinge region of the heavy chain IgG1 gene and expressed in eukaryotic cells (Renzetti, et al., 1997, Inflamm. Res. 46: S143).
IL-1 has been implicated as an immunological effector molecule in a large number of disease processes. IL-1 receptor antagonist (IL-1ra) had been examined in human clinical trials. Efficacy has been demonstrated for the treatment of rheumatoid arthritis (Antril, Amgen). In a phase III human clinical trial IL-1ra reduced the mortality rate in patients with septic shock syndrome (Dinarello, 1995, Nutrution 11, 492). Osteoarthritis is a slow progressive disease characterized by destruction of the articular cartilage. IL-1 is detected in synovial fluid and in the cartilage matrix of osteoarthritic joints. Antagonists of IL-1 have been shown to diminish the degradation of cartilage matrix components in a variety of experimental models of arthritis (Chevalier, 1997, Biomed Pharmacother. 51, 58). Nitric oxide (NO) is a mediator of cardiovascular homeostasis, neurotransmission and immune function; recently it has been shown to have important effects in the modulation of bone remodeling. Cytokines such as IL-1 and TNF are potent stimulators of NO production. NO is an important regulatory molecule in bone with effects on cells of the osteoblast and osteoclast lineage (Evans, et al., 1996, J Bone Miner Res. 11, 300). The promotion of beta-cell destruction leading to insulin dependent diabetes mellitus shows dependence on IL-1. Some of this damage may be mediated through other effectors such as prostaglandins and thromboxanes. IL-1 can effect this process by controlling the level of both cyclooxygenase II and inducible nitric oxide synthetase expression (McDaniel et al., 1996, Proc Soc Exp Biol Med. 211, 24).
Inhibitors of cytokine production are expected to block inducible cyclooxygenase (COX-2) expression. COX-2 expression has been shown to be increased by cytokines and it is believed to be the isoform of cyclooxygenase responsible for inflammation (M. K. O""Banion et al., Proc. Natl. Acad. Sci. U.S.A, 1992, 89, 4888.) Accordingly, inhibitors of cytokines such as IL-1 would be expected to exhibit efficacy against those disorders currently treated with COX inhibitors such as the familiar NSAIDs. These disorders include acute and chronic pain as well as symptoms of inflammation and cardiovascular disease.
Elevation of several cytokines have been demonstrated during active inflammatory bowel disease (IBD). A mucosal imbalance of intestinal IL-1 and IL-1ra is present in patients with IBD. Insufficient production of endogenous IL-1ra may contribute to the pathogenesis of IBD (Cominelli, et al., 1996, Aliment Pharmacol Ther. 10, 49). Alzheimer disease is characterized by the presence of beta-amyloid protein deposits, neurofibrillary tangles and cholinergic dysfunction throughout the hippocampal region. The structural and metabolic damage found in Alzheimer disease is possibly due to a sustained elevation of IL-1 (Holden, et al., 1995, Med Hypotheses, 45, 559). A role for IL-1 in the pathogenesis of human immunodeficiency virus (HIV) has been identified. IL-1ra showed a clear relationship to acute inflammatory events as well as to the different disease stages in the pathophysiology of HIV infection (Kreuzero, et al., 1997, Clin Exp Immunol. 109, 54). IL-1 and TNF are both involved in periodontal disease. The destructive process associated with periodontal disease may be due to a disregulation of both IL-1 and TNF (Howells, 1995, Oral Dis. 1, 266).
Proinflammatory cytokines such as TNFxcex1 and IL-1xcex2 a are also important mediators of septic shock and associated cardiopulmonary dysfunction, acute respiratory distress syndrome (ARDS) and multiple organ failure. In a study of patients presenting at a hospital with sepsis, a correlation was found between TNFxcex1 and IL-6 levels and septic complications (Terregino et al., 2000, Ann. Emerg. Med., 35, 26). TNFxcex1 has also been implicated in cachexia and muscle degradation, associated with HIV infection (Lahdiverta et al., 1988, Amer. J. Med., 85, 289). Obesity is associated with an increase incidence of infection, diabetes and cardiovascular disease. Abnormalities in TNFxcex1 expression have been noted for each of the above conditions (Loffreda, et al., 1998, FASEB J. 12, 57). It has been proposed that elevated levels of TNFxcex1 are involved in other eating related disorders such as anorexia and bulimia nervosa. Pathophysiological parallels are drawn between anorexia nervosa and cancer cachexia (Holden, et al., 1996, Med Hypotheses 47, 423). An inhibitor of TNFxcex1 production, HU-211, was shown to improve the outcome of closed brain injury in an experimental model (Shohami, et al., 1997, J Neuroimmunol. 72, 169). Atherosclerosis is known to have an inflammatory component and cytokines such as IL-1 and TNF have been suggested to promote the disease. In an animal model an IL-1 receptor antagonist was shown to inhibit fatty streak formation (Elhage et al., 1998, Circulation, 97, 242).
TNFxcex1 levels are elevated in airways of patients with chronic obstructive pulmonary disease and it may contribute to the pathogenesis of this disease (M. A. Higham et al., 2000, Eur. Respiratory J., 15, 281). Circulating TNFxcex1 may also contribute to weight loss associated with this disease (N. Takabatake et al., 2000, Amer. J. Resp. and Crit. Care Med.,161 (4 Pt 1), 1179). Elevated TNFxcex1 levels have also been found to be associated with congestive heart failure and the level has been correlated with severity of the disease (A. M. Feldman et al., 2000, J. Amer. College of Cardiology, 35, 537). In addition, TNFxcex1 has been implicated in reperfusion injury in lung (Borjesson et al., 2000, Amer. J. Physiol., 278, L3-12), kidney (Lemay et al., 2000, Transplantation, 69, 959), and the nervous system (Mitsui et al., 1999, Brain Res., 844, 192).
TNFxcex1 is also a potent osteoclastogenic agent and is involved in bone resorption and diseases involving bone resorption (Abu-Amer et al., 2000, J. Biol. Chem., 275, 27307). It has also been found highly expressed in chondrocytes of patients with traumatic arthritis (Melchiorri et al., 2000, Arthritis and Rheumatism, 41, 2165). TNFxcex1 has also been shown to play a key role in the development of glomerulonephritis (Le Hir et al., 1998, Laboratory Investigation, 78, 1625).
The abnormal expression of inducible nitric oxide synthetase (iNOS) has been associated with hypertension in the spontaneously hypertensive rat (Chou et al., 1998, Hypertension, 31, 643). IL-1 has a role in the expression of iNOS and therefore may also have a role in the pathogenesis of hypertension (Singh et al., 1996, Amer. J. Hypertension, 9, 867).
IL-1 has also been shown to induce uveitis in rats which could be inhibited with IL-1 blockers. (Xuan et al., 1998, J. Ocular Pharmacol. and Ther., 14, 31). Cytokines including IL-1, TNF and GM-CSF have been shown to stimulate proliferation of acute myclogenous leukemia blasts (Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was shown to be essential for the development of both irritant and allergic contact dermatitis. Epicutaneous sensitization can be prevented by the administration of an anti-IL-1 monoclonal antibody before epicutaneous application of an allergen (Muller, et al., 1996, Am J Contact Dermat. 7, 177). Data obtained from IL-1 knock out mice indicates the critical involvement in fever for this cytokine (Kluger et al., 1998, Clin Exp Pharmacol Physiol. 25, 141). A variety of cytokines including TNF, IL-1, IL-6 and IL-8 initiate the acute-phase reaction which is stereotyped in fever, malaise, myalgia, headaches, cellular hypermetabolism and multiple endocrine and enzyme responses (Beisel, 1995, Am J Clin Nutr. 62, 813). The production of these inflammatory cytokines rapidly follows trauma or pathogenic organism invasion.
Other proinflammatory cytokines have been correlated with a variety of disease states. IL-8 correlates with influx of neutrophils into sites of inflammation or injury. Blocking antibodies against IL-8 have demonstrated a role for IL-8 in the neutrophil associated tissue injury in acute inflammation (Harada et al., 1996, Molecular Medicine Today 2, 482). Therefore, an inhibitor of IL-8 production may be useful in the treatment of diseases mediated predominantly by neutrophils such as stroke and myocardial infarction, alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion associated syndromes, and necrotizing enterocolitis.
Rhinovirus triggers the production of various proinflammatory cytokines, predominantly IL-8, which results in symptomatic illnesses such as acute rhinitis (Winther et al., 1998, Am J Rhinol. 12, 17).
Other diseases that are effected by IL-8 include myocardial ischemia and reperfusion, inflammatory bowel disease and many others.
The proinflammatory cytokine IL-6 has been implicated with the acute phase response. IL-6 is a growth factor in a number in oncological diseases including multiple mycloma and related plasma cell dyscrasias (Treon, et al., 1998, Current Opinion in Hematology 5: 42). It has also been shown to be an important mediator of inflammation within the central nervous system. Elevated levels of IL-6 are found in several neurological disorders including AIDS dementia complex, Alzheimer""s disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma and viral and bacterial meningitis (Gruol, et al., 1997, Molecular Neurobiology 15: 307). IL-6 also plays a significant role in osteoporosis. In murine models it has been shown to effect bone resorption and to induce osteoclast activity (Ershler et al., 1997, Development and Comparative Immunol. 21: 487). Marked cytokine differences, such as IL-6 levels, exist in vivo between osteoclasts of normal bone and bone from patients with Paget""s disease (Mills, et al., 1997, Calcif Tissue Int. 61, 16). A number of cytokines have been shown to be involved in cancer cachexia. The severity of key parameters of cachexia can be reduced by treatment with anti IL-6 antibodies or with IL-6 receptor antagonists (Strassmann, et al., 1995, Cytokins Mol Ther. 1, 107). Several infectious diseases, such as influenza, indicate IL-6 and IFN alpha as key factors in both symptom formation and in host defense (Hayden, et al., 1998, J Clin Invest. 101, 643). Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman""s disease, psoriasis and post-menopausal osteoporosis (Simpson, et al., 1997, Protein Sci. 6, 929). Compounds that interfered with the production of cytokines including IL-6, and TNF were effective in blocking a passive cutaneous anaphylaxis in mice (Scholz et al., 1998, J. Med. Chem., 41, 1050).
GM-CSF is another proinflammatory cytokine with relevance to a number of therapeutic diseases. It influences not only proliferation and differentiation of stem cells but also regulates several other cells involved in acute and chronic inflammation. Treatment with GM-CSF has been attempted in a number of disease states including bum-wound healing, skin-graft resolution as well as cytostatic and radiotherapy induced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF also appears to play a role in the replication of human immunodeficiency virus (HIV) in cells of macrophage lineage with relevance to AIDS therapy (Crowe et al., 1997, Journal of Leukocyte Biology 62, 41). Bronchial asthma is characterised by an inflammatory process in lungs. Involved cytokines include GM-CSF amongst others (Lee, 1998, J R Coll Physicians Lond 32, 56).
Interferon xcex3 (IFN xcex3) has been implicated in a number of diseases. It has been associated with increased collagen deposition that is a central histopathological feature of graft-versus-host disease (Parkman, 1998, Curr Opin Hematol. 5, 22). Following kidney transplantation, a patient was diagnosed with acute myelogenous leukemia. Retrospective analysis of peripheral blood cytokines revealed elevated levels of GM-CSF and IFN xcex3. These elevated levels coincided with a rise in peripheral blood white cell count (Burke, et al., 1995, Leuk Lymphoma. 19, 173). The development of insulin-dependent diabetes (Type 1) can be correlated with the accumulation in pancreatic islet cells of T-cells producing IFN xcex3 (Ablumunits, et al., 1998, J Autoimmun. 11, 73). IFN xcex3 along with TNF, IL-2 and IL-6 lead to the activation of most peripheral T-cells prior to the development of lesions in the central nervous system for diseases such as multiple sclerosis (MS) and AIDS dementia complex (Martino et al., 1998, Ann Neurol. 43, 340). Atherosclerotic lesions result in arterial disease that can lead to cardiac and cerebral infarction. Many activated immune cells are present in these lesions, mainly T-cells and macrophages. These cells produce large amounts of proinflammatory cytokines such as TNF, IL-1 and IFN xcex3. These cytokines are thought to be involved in promoting apoptosis or programmed cell death of the surrounding vascular smooth muscle cells resulting in the atherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76). Allergic subjects produce mRNA specific for IFN xcex3 following challenge with Vespula venom (Bonay, et al., 1997, Clin Exp Immunol. 109, 342). The expression of a number of cytokines, including IFN xcex3 has been shown to increase following a delayed type hypersensitivity reaction thus indicating a role for IFN xcex3 in atopic dermatitis (Szepietowski, et al., 1997, Br J Dermatol. 137, 195). Histopathologic and immunohistologic studies were performed in cases of fatal cerebral malaria. Evidence for elevated IFN xcex3 amongst other cytokines was observed indicating a role in this disease (Udomsangpetch et al., 1997, Am J Trop Med Hyg. 57, 501). The importance of free radical species in the pathogenesis of various infectious diseases has been established. The nitric oxide synthesis pathway is activated in response to infection with certain viruses via the induction of proinflammatory cytokines such as IFN xcex3 (Akaike, et al., 1998, Proc Soc Exp Biol Med. 217, 64). Patients, chronically infected with hepatitis B virus (HBV) can develop cirrhosis and hepatocellular carcinoma. Viral gene expression and replication in HBV transgenic mice can be suppressed by a post-transcriptional mechanism mediated by IFN xcex3, TNF and IL-2 (Chisari, et al., 1995, Springer Semin Immunopathol. 17, 261). IFN xcex3 can selectively inhibit cytokine induced bone resorption. It appears to do this via the intermediacy of nitric oxide (NO) which is an important regulatory molecule in bone remodeling. NO may be involved as a mediator of bone disease for such diseases as: the rheumatoid arthritis, tumor associated osteolysis and postmenopausal osteoporosis (Evans, et al., 1996, J Bone Miner Res. 11, 300). Studies with gene deficient mice have demonstrated that the IL-12 dependent production of IFN xcex3 is critical in the control of early parasitic growth. Although this process is independent of nitric oxide the control of chronic infection does appear to be NO dependent (Alexander et al., 1997, Philos Trans R Soc Lond B Biol Sci 352, 1355). NO is an important vasodilator and convincing evidence exists for its role in cardiovascular shock (Kilbourn, et al., 1997, Dis Mon. 43, 277). IFN xcex3 is required for progression of chronic intestinal inflammation in such diseases as Crohn""s disease and inflammatory bowel disease (IBD) presumably through the intermediacy of CD4+ lymphocytes probably of the TH 1 phenotype (Sartor 1996, Aliment Pharmacol Ther. 10 Suppl 2, 43). An elevated level of serum IgE is associated with various atopic diseases such as bronchial asthma and atopic dermatitis. The level of IFN xcex3 was negatively correlated with serum IgE suggesting a role for IFN xcex3 in atopic patients (Teramoto et al., 1998, Clin Exp Allergy 28, 74).
WO 01/01986 discloses particular compounds alleged to having the ability to inhibit TNFxcex1. The specific inhibitors disclosed are structurally distinct from the novel compounds disclosed in the present application disclosed hereinbelow. Certain compounds disclosed in WO 01/01986 are indicated to be effective in treating the following diseases: dementia associated with HIV infection, glaucoma, optic-neuropathy, optic neuritis, retinal ischemia, laser induced optic damage, surgery or trauma-induced proliferative vitreoretinopathy, cerebral ischemia, hypoxia-ischemia, hypoglycemia, domoic acid poisoning, anoxia, carbon monoxide or manganese or cyanide poisoning, Huntington""s disease, Alzheimer""s disease, Parkinson""s disease, meningitis, multiple sclerosis and other demyelinating diseases, amyotrophic lateral sclerosis, head and spinal cord trauma, seizures, convulsions, olivopontocerebellar atrophy, neuropathic pain syndromes, diabetic neuropathy, HIV-related neuropathy, MERRF and MELAS syndromes, Leber""s disease, Wemicke""s encephalophathy, Rett syndrome, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett""s syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety and schizophrenia. WO 02/32862 discloses that inhibitors of pro-inflammatory cytokines including TNFxcex1 are allegedly useful for treating acute and chronic inflammation in the lung caused by inhalation of smoke such as cigarette smoke.
Compounds which modulate release of one or more of the aforementioned inflammatory cytokines can be useful in treating diseases associated with release of these cytokines. For example, WO 98/52558 discloses heteroaryl urea compounds which are indicated to be useful in treating cytokine mediated diseases. WO 99/23091 discloses another class of urea compounds which are useful as anti-inflammatory agents. WO 99/32463 relates to aryl ureas amd their use in treating cytokine diseases and proteolytic enzyme mediated disease. WO 00/41698 discloses aryl ureas said to be useful in treating p38 MAP kinase diseases.
U.S. Pat. No. 5,162,360 discloses N-substituted aryl-Nxe2x80x2-heterocyclic substituted urea compounds which are described as being useful for treating hypercholesterolemia and atheroclerosis.
The work cited above supports the principle that inhibition of cytokine production will be beneficial in the treatment of various disease states. Some protein therapeutics are in late development or have been approved for use in particular diseases. Protein therapeutics are costly to produce and have bioavailability and stability problems. Therefore a need exists for new small molecule inhibitors of cytokine production with optimized efficacy, pharmacokinetic and safety profiles.
The work cited above supports the principle that inhibition of cytokine production will be beneficial in the treatment of various disease states.
It is therefore an object of the invention to provide novel compounds which inhibit the release of inflammatory cytokines such as interleukin-1 and tumor necrosis factor.
It is a further object of the invention to provide methods for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease, using the novel compounds of the invention.
It is yet a further object of the invention to provide processes of preparation of the above-mentioned novel compounds.
In the broadest generic aspect of the invention, there are provided compounds of the formula (I): 
wherein:
n is 1, 2, 3, 4 or 5 such that the cycloalkyl group is chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each optionally independently substituted by one to two R1 or R2;
X is O;
p is 0 or 1;
z is 0 or 1;
m is 0, 1 or 2;
ring A is:
fused saturated or unsaturated ring containing 3-5 carbon atoms wherein ring A or the phenyl ring to which it is fused is optionally substituted by one or more C1-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C1-6 branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl, phenylsulfonyl, hydroxy, amino, mono- or di-(C1-4 alkyl)amino, mono- or di-(C1-4 alkyl)amino-S(O)2, cyano, nitro or H2NSO2;
Preferred formula (I) compounds are those where ring A and the phenyl ring to which it is fused form: 
L is:
(i) a bond or an acyclic group chosen from: xe2x80x94Oxe2x80x94; xe2x80x94NHxe2x80x94;  greater than C(O);  greater than C(S);
C1-10 saturated or unsaturated branched or unbranched carbon chain;
wherein one or more carbon atoms are optionally independently replaced by heteroatoms chosen from O, N and S(O)m; and
wherein said acyclic group is optionally substituted with 0-2 oxo groups, one or more C1-4 branched or unbranched alkyl optionally substituted by one or more halogen atoms, hydroxy, amino or imino;
or L is
(ii) a cyclic group chosen from: a C5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C1-4 alkyl, C11-4 alkoxy or C1-4 alkylamino chains each being branched or unbranched;
aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, piperdinyl, benzimidazole, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, oxo, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen;
with the proviso that:
when L is (i), then p is 0;
and when L is (ii), then z is 0;
J is chosen from xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH(CH3)xe2x80x94, xe2x80x94CH2CH(OH)xe2x80x94, xe2x80x94CH(OH)xe2x80x94 and  greater than C(O);
Q is
phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, benzimidazolyl, furanyl, thienyl, pyranyl, thiazolyl, oxazolyl, naphthyridinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5-b]pyridinyl, 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, 2-thia-5-aza-bicyclo[2.2.1]heptanyl, imidazo[4,5-b]pyridinyl, 1-oxo-xcex4-thiomorpholinyl or 13-oxa-11-aza-tricyclo[7.3.1.0-2,7]trideca-2,4,6-triene tetrahydropyranyl, 2-oxo-2H-pyranyl, tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, piperazinyl, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone each optionally substituted with one to three oxo, C1-6 alkyl, phenyl, C1-6 alkoxy or hydroxy;
or Q is C1-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C1-3 alkyl or C1-5 alkoxyalkyl, phenylamino, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino;
R1 is
phenyl, benzyl, naphthyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, piperidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl, thienyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-7 cycloalkylC0-2 alkyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alky)lamino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl) aminocarbonyl, C1-5 alkyl-C(O)xe2x80x94C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-5alkyl)amino, mono- or di-(C1-3alkyl)amino-C1-5 alkyl, C1-5 alkyl-S(O)m, amino-S(O)m, di-(C1-3alkyl)amino-S(O)m, R3xe2x80x94C1-5alkyl, R3xe2x80x94C1-5 alkoxy, R3C(O)xe2x80x94C1-5 alkyl, R3xe2x80x94C1-5 alkyl(R4)N, C1-6 acyl, C1-6 alkoxyC1-3 acyl, carboxy-mono- or di-(C1-5alkyl)-amino;
C3-7 cycloalkylC0-5 alkyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups;
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
C1-4 alkyl-phenyl-C(O)xe2x80x94C1-4 alkyl-, C1-4 alkyl-C(O)xe2x80x94C1-4 alkyl- or C1-4 alkyl-phenyl-S(O)mxe2x80x94C1-4 alkyl-;
C1-6 alkyl or C1-6 alkoxy each of which is branched or unbranched and optionally partially or fully halogenated or optionally substituted with R3;
R2, is
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, C6acyl, aroyl, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, carboxy, nitrile, nitro, halogen, C1-6 alkoxycarbonyl, C1-6 alkyl-S(O)m optionally partially or fully halogenated, phenyl-S(O)m, amino or aminocarbonyl wherein the N atom is optionally mono-or-disubstituted by C1-6 branched or unbranchcd alkyl, C1-6acyl, phenyl or benzyl;
each R3 is independently:
nitrile, C3-7 cycloalkyl, phenyl or NR5R6;
each R4 is independently:
hydrogen or C1-4 alkyl optionally partially or fully halogenated;
Y, if present, is covalently attached to Q, and is
a bond, xe2x80x94Oxe2x80x94,  greater than C(O), xe2x80x94NHxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, C1-5 alkyl branched or unbranched, C1-3 alkyl(OH), C2-5 alkenyl, C1-3 acyl, heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl or tetrahydrofuryl, heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiofuranyl, quinoxalinyl, quinazolinyl or indazolyl or aryl each alkyl, alkenyl, acyl, heterocycle, heteroaryl and aryl are optionally substituted by one to three hydroxy, oxo, C1-4 alkyl, C1-3 alkoxy, C1-4 acyl, C1-5 alkoxycarbonyl, NR5R6 or NR5R6xe2x80x94C(O)xe2x80x94;
wherein each Y is optionally further covalently attached to NR5R6, C1-4 alkyl, C3-7 cycloalkylC0-4 alkyl, C1-4 alkoxy, aryloxy, hydroxy, arylC0-4 alkyl, heteroarylC0-4 alkyl or heterocycleC0-4 alkyl as wherein the heteroaryl and heterocycle moieties are as hereinabove described for Y and the heterocycle, heteroaryl and aryl moieties are optionally substituted by one to three hydroxy, oxo, C1-3 alkyl, C1-3 alkoxy, C1-5 alkoxycarbonyl, NR5R6 or NR5R6xe2x80x94C(O)xe2x80x94;
each R5 and R6 are independently hydrogen, C3-7 cycloalkylC0-4 alkyl, arylC0-3 alkyl optionally subtituted by halogen, C1-3 alkyl or diC1-5 alkyl amino, or R5 and R6 are C1-3 acyl, aroyl or C1-6 branched or unbranched alkyl optionally substituted by C1-5 alkoxy, hydroxy, mono- or di-C1-3alkylaminocarbonyl or mono or diC1-3 alkyl amino wherein said C1-6 alkyl optionally partially or fully halogenated;
or R5 and R6 taken together optionally form a heteroring chosen from morpholinyl, morpholino, thiomorpholino, piperidinyl, pyridazinyl, pyrimidinyl, imidazolyl, pyridinyl, tetrazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrrolyl and pyrrolidinyl;
and the pharmaceutically acceptable derivatives thereof.
In a first subgeneric aspect of the invention, there are provided compounds of the formula (I) as described in the broadest generic aspect above and wherein:
L is (i);
z is 0 or 1;
n is 1, 2 or 3, such that the cycloalkyl group is chosen from cyclopropyl, cyclobutyl and cyclopentyl, each optionally independently substituted by one to two R1 or R2;
ring A is: 
Q is
phenyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, benzimidazolyl, thiazolyl, oxazolyl, naphthyridinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, piperazinyl, piperidinyl, piperidinonyl, dihydropyrimidonyl or tetrahydropyrimidonyl which are optionally substituted with one to three C1-6 alkyl, phenyl, C1-6 alkoxy or hydroxy;
R1 is
phenyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl or indazolyl, each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-7 cycloalkyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alky)lamino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl) aminocarbonyl, C1-5 alkyl-C(O)xe2x80x94C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-5alkyl)amino, mono- or di-(C1-3alkyl)amino-C1-5 alkyl, amino-S(O)2 or di-(C1-3alkyl)amino-S(O)2;
C3-7 cycloalkyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups;
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
C1-6 alkyl branched or unbranched and optionally partially or fully halogenated;
R2, is
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, C1-6acyl, aroyl, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, carboxy, nitrile, nitro, halogen.
In another embodiment of the invention there is provided compounds of the formula(I) as described immediately above, and wherein:
n is 1, such that the cycloalkyl group is cyclopropyl optionally independently substituted by one to two R1 or R2;
ring A is: 
L is:
xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94,  greater than C(O),  greater than C(S), xe2x80x94OCH2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94C(CH3)2xe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x80x94CH2CH(OH)xe2x80x94, xe2x80x94CH(OH)CH2xe2x80x94, xe2x80x94OCH2CH2xe2x80x94, xe2x80x94OCH2CH2CH2xe2x80x94, xe2x80x94OCH2CH2(CH3)xe2x80x94, xe2x80x94OCH2(CH3)CH2xe2x80x94, xe2x80x94OCH2C(O)xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHCH2CH2, xe2x80x94NHxe2x80x94, xe2x80x94NHCH2xe2x80x94, xe2x80x94NHCH2CH2xe2x80x94, xe2x80x94S(O)mxe2x80x94, xe2x80x94S(O)mCH2xe2x80x94, xe2x80x94S(O)mCH2CH2xe2x80x94 and xe2x80x94S(O)mCH2CH2CH2xe2x80x94;
Q is
phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, piperazinyl, piperidinyl, piperidinonyl, dihydropyrimidonyl or tetrahydropyrimidonyl which are optionally substituted with one to three C1-4 alkyl, phenyl, C1-4 alkoxy or hydroxy;
R1 is
phenyl optionally substituted with one to three C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-7 cycloalkyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally partially or fully halogenated, nitro, amino or mono- or di-(C1-3alky)lamino;
C3-7 cycloalkyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups;
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
C1-6 alkyl branched or unbranched and optionally partially or fully halogenated; and
R2, is
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, carboxy, nitrile, nitro, halogen.
In yet another embodiment of the invention there is provided compounds of the formula(I) as described immediately above, and wherein:
L is:
xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94,  greater than C(O), xe2x80x94OCH2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x80x94CH2CH(OH)xe2x80x94, xe2x80x94CH(OH)CH2xe2x80x94, xe2x80x94OCH2CH2xe2x80x94, xe2x80x94OCH2CH2CH2xe2x80x94, xe2x80x94OCH2CH2(CH3)xe2x80x94, xe2x80x94OCH2(CH3)CH2xe2x80x94, xe2x80x94S(O)mxe2x80x94, xe2x80x94S(O)mCH2xe2x80x94, S(O)mCH2CH2xe2x80x94 and xe2x80x94S(O)mCH2CH2CH2xe2x80x94;
Q is
pyridinyl, pyrimidinyl, dihydropyrimidonyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide or thiomorpholinyl sulfone which are optionally substituted with one to two C1-4 alkoxy or C1-4 alkyl;
R1 is
phenyl, C3-7 cycloalkyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups;
C1-6 alkyl branched or unbranched and optionally partially or fully halogenated; and
R2, is
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, carboxy, nitrile, nitro, halogen.
In still yet another embodiment of the invention there is provided compounds of the formula(I) as described immediately above, and wherein:
n is 1, such that the cycloalkyl group is cyclopropyl which is substituted by one R1;
z is 0;
L is:
xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94,  greater than C(O) and xe2x80x94OCH2CH2xe2x80x94;
Q is
pyridinyl, pyrimidinyl, dihydropyrimidonyl or morpholinyl which are optionally substituted with one to two C1-4 alkoxy or C1-4 alkyl;
R1 is
phenyl, C3-6 cycloalkyl or neopentyl each being optionally partially or fully halogenated.
In yet another embodiment of the invention there is provided compounds of the formula(I) as described immediately above, and wherein:
Q is
pyridin-4-yl, pyrimidin-4-yl or morpholin-4-yl which are optionally substituted with one to two C1-4 alkoxy or C1-4 alkyl; and
R1 is
phenyl, cyclohexyl or neopentyl each being optionally partially or fully halogenated.
In still yet another embodiment of the invention there is provided compounds of the formula(I) wherein:
n is 1, such that the cycloalkyl group is cyclopropyl which is substituted by one R1;
z is 1;
Y is:
a bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94,  greater than C(O),
wherein each Y is further covalently attached to NR5R6, piperazinylC0-2 alkyl, piperidinylC0-2 alkyl, pyrrolidinylC0-2 alkyl, each abovelisted heterocycle is optionally substituted by one to two acetyl, methyl, ethyl, halogen or hydroxy;
each R5 and R6 are independently hydrogen, C3-5 cycloalkylC1-2 alkyl, benzyl each optionally subtituted by chlorine, bromine, fluorine or C1-2 alkyl, acetyl, benzoyl or C1-4 branched or unbranched alkyl;
L is:
xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94,  greater than C(O) and xe2x80x94OCH2CH2xe2x80x94;
Q is
pyridinyl, triazinyl or pyrimidinyl which are optionally substituted with one to two C1-4 alkoxy or C1-4 alkyl;
R1 is
phenyl, C3-6 cycloalkyl or neopentyl each being optionally partially or fully halogenated.
In yet another embodiment of the invention there is provided compounds of the formula(I) as described immediately above, and wherein:
L is xe2x80x94Oxe2x80x94;
Q is
pyridin-4-yl, pyrimidin-4-yl or triazin-2-yl which are optionally substituted with one to two C1-4 alkoxy or C1-4 alkyl; and
R1 is cyclohexyl and
Y is:
a bond, xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94,  greater than C(O),
wherein each Y is further covalently attached to NR5R6, piperazinyl, piperidinyl, pyrrolidinyl, each abovelisted heterocycle is optionally substituted by methyl, ethyl or hydroxy;
each R5 and R6 are independently hydrogen, cyclopropylmethyl, benzyl, benzoyl or C1-3 alkyl.
Table I contains representative compounds of the invention wherein L is (i) which can be made by according to the general methods and examples in the sections below.
or the pharmaceutically acceptable derivatives thereof.
Table II contains further representative compounds of the invention wherein L is (i) which can be made by according to the general methods and examples in the sections below.
or the pharmaceutically acceptable derivatives thereof.
In a second subgeneric aspect of the invention, there are provided compounds of the formula (I) as described in the broadest generic aspect and wherein:
L is (ii);
n is 1, 2, 3, such that the cycloalkyl group is chosen from cyclopropyl, cyclobutyl and cyclopentyl, each optionally independently substituted by one to two R1 or R2;
p is 0 or 1;
ring A is: 
Q is
phenyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, benzimidazolyl, thiazolyl, oxazolyl, naphthyridinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, piperazinyl, piperidinyl or tetrahydropyranyl which are optionally substituted with one to three C1-6 alkyl, phenyl, C1-6 alkoxy or hydroxy;
J is
xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94;
R1 is
phenyl, benzyl, tetrahydrofuranyl, tetrahydropyranyl, morpholino, pyridinyl, pyrimidinyl, piperidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, thiazolyl, oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl or indazolyl, each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-7 cycloalkylC0-2 alkyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, C1-5 acyl, C1-5 alkoxycarbonyl, C1-5 alkylS(O)mxe2x80x94, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alky)lamino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl) aminocarbonyl, C1-5 alkyl-C(O)xe2x80x94C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-5alkyl)amino, mono- or di-(C1-3alkyl)amino-C1-5 alkyl, amino-S(O)2 or di-(C1-3alkyl)amino-S(O)2;
C3-7 cycloalkylC0-2 alkyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups;
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
C1-6 alkyl branched or unbranched and optionally partially or fully halogenated; and
R2 is
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, C1-6acyl, aroyl, C1-5 branched or unbranched alkoxy, each being optionally partially or fully halogenated, carboxy, nitrile, nitro, amino or halogen.
In another embodiment of the invention there is provided compounds of the formula(I) as described immediately above, and wherein:
n is 1, such that the cycloalkyl group is cyclopropyl optionally independently substituted by one to two R1 or R2;
ring A is: 
L is:
aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, piperidinyl, benzimidazole, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, oxo, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen;
Q is
phenyl, pyridinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone or tetrahydropyranyl each of which are optionally substituted with one to three C1-4 alkyl, phenyl, C1-4 alkoxy or hydroxy;
R1 is
phenyl, benzyl, tetrahydrofuranyl, tetrahydropyranyl, morpholino, pyridinyl, piperidinyl, pyrrolidinyl or thienyl each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-7 cycloalkylC0-2 alkyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, C1-5 acyl, C1-5 alkoxycarbonyl, C1-5 alkylS(O)mxe2x80x94, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alky)lamino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl) aminocarbonyl, C1-5 alkyl-C(O)xe2x80x94C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-5alkyl)amino, mono- or di-(C1-3alkyl)amino-C1-5alkyl, amino-S(O)2 or di-(C1-3alkyl)amino-S(O)2;
C3-7 cycloalkylC0-2 alkyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups;
C1-6 alkyl branched or unbranched and optionally partially or fully halogenated; and
R2is
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, C1-5 branched or unbranched alkoxy, each being optionally partially or fully halogenated, carboxy, nitrile, nitro, halogen or amino.
In yet another embodiment of the invention there is provided compounds of the formula(I) as described immediately above, and wherein:
L is:
aryl, pyridinyl, pyrimidinyl or piperidinyl each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, oxo, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O), or halogen;
Q is
morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydropyranyl each of which are optionally substituted with one to three C1-4 alkyl;
R1 is
phenyl, benzyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl or thienyl each of the aforementioned is optionally substituted with one to three C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-7 cycloalkylC0-2 alkyl, C1-5 acyl, C1-5 alkoxycarbonyl, C1-5 alkylS(O)mxe2x80x94, halogen, C1-3 alkoxy, nitro, amino, mono- or di-(C1-3alky)lamino, NH2C(O) or a mono- or di-(C1-3alkyl) aminocarbonyl;
C3-7 cycloalkylC0-2 alkyl optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups;
C1-6 alkyl branched or unbranched and optionally partially or fully halogenated; and
R2 is
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, C1-5 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen or amino.
In still yet another embodiment of the invention there is provided compounds of the formula(I) as described immediately above, and wherein:
n is 1, such that the cycloalkyl group is cyclopropyl which is substituted by one to two R1 or R2;
L is piperidinyl or 2-oxo-1,2-dihydropyridinyl;
Q is
tetrahydropyranyl or morpholinyl which are optionally substituted with one to three C1-4 alkyl;
R1 is
C1-5 alkyl, phenyl, benzyl, cyclohexylC0-2 alkyl, cyclopentyl C0-2 alkyl, tetrahydrofuranyl, thienyl, or R1 is pyrrolidinyl or piperidinyl optionally substituted by C1-4 acyl, C1-5 alkoxycarbonyl or C1-3 alkylsulfonyl; and
R2 is C1-5 alkyl, C1-5 alkoxy, halogen or amino.
In yet another embodiment of the invention there is provided compounds of the formula(I) as described immediately above, and wherein:
Q is
tetrahydropyran-4-yl or morpholin-4-yl which are optionally substituted with one to three C1-4 alkyl;
J is xe2x80x94CH2xe2x80x94;
R1 is
neopentyl, tert-butyl, sec-butyl, 1,2-dimethylpropyl, isobutyl, phenyl, benzyl, cyclohexylC0-1 alkyl, cyclopentyl C0-1, alkyl, tetrahydrofuranyl, thienyl, or R1 is pyrrolidinyl or piperidinyl optionally substituted by C1-4 acyl, tert-butoxycarbonyl or C1-2 alkylsulfonyl;
R2 is methyl, methoxy, chlorine, bromine or amino; and
L is piperidin-3-yl or 2-oxo-1,2-dihydropyridin-4-yl.
Table III contains representative compounds of the invention wherein L is (ii) which can be made by according to the general methods and examples in the sections below.
or the pharmaceuticaly acceptable derivatives thereof.
In all the compounds disclosed hereinabove in this application, in the event the nomenclature is in conflict with the structure, it shall be understood that the compound is defined by the structure.
Any compounds of this invention containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.
Some of the compounds of formula (I) can exist in more than one tautomeric form. The invention includes all such tautomers.
All terms as used herein in this specification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. For example, xe2x80x9cC1-4alkoxyxe2x80x9d is a C1-4alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, and butoxy. All alkyl, alkenyl and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows:
The term xe2x80x9caroylxe2x80x9d as used in the present specification shall be understood to mean xe2x80x9cbenzoylxe2x80x9d or xe2x80x9cnaphthoylxe2x80x9d.
The term xe2x80x9ccarbocyclexe2x80x9d shall be understood to mean an aliphatic hydrocarbon radical containing from three to twelve carbon atoms. Carbocycles include hydrocarbon rings containing from three to ten carbon atoms. These carbocycles may be either aromatic or non-aromatic ring systems. The non-aromatic ring systems may be mono- or polyunsaturated. Preferred carbocycles unless otherwise specified include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl.
The term xe2x80x9cheterocyclexe2x80x9d refers to a stable nonaromatic 4-8 membered (but preferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 membered bicyclic heterocycle radical which may be either saturated or unsaturated. Each heterocycle consists of carbon atoms and one or more, preferably from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle may be attached by any atom of the cycle, which results in the creation of a stable structure. Preferred heterocycles unless otherwise specified include but are not limited to, for example oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl and dithianyl.
The term xe2x80x9cheteroarylxe2x80x9d shall be understood to mean an aromatic 5-8 membered monocyclic or 8-11 membered bicyclic ring containing 1-4 heteroatoms chosen from N, O and S. Included are the partially or fully saturated derivates thereof. Such heteroaryls unless otherwise specified include: pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benz[1,4]oxazin-3-onyl, benzodioxolyl, benz[1,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl and phthalimidyl.
The term xe2x80x9cheteroatomxe2x80x9d as used herein shall be understood to mean atoms other than carbon such as O, N, S and P.
The term xe2x80x9carylxe2x80x9d as used herein unless otherwise specified shall be understood to mean aromatic carbocycle or heteroaryl as defined herein.
Terms which are analogs of the above cyclic moieties such as aryloxy, heterocyclyloxy or heteroaryl amine shall be understood to mean an aryl, heteroaryl, heterocycle as defined above attached to it""s respective group.
As used herein, xe2x80x9cnitrogenxe2x80x9d and xe2x80x9csulfurxe2x80x9d include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen. For example, if Y is xe2x80x94Sxe2x80x94C1-6 alkyl, unless otherwise specified, this shall be understood to include xe2x80x94S(O)xe2x80x94C1-6 alkyl and xe2x80x94S(O)2xe2x80x94C1-6 alkyl.
The term xe2x80x9chalogenxe2x80x9d as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine. The definitions xe2x80x9cpartially or fully halogenatedxe2x80x9d xe2x80x9csubstituted by one or more halogen atomsxe2x80x9d includes for example, mono, di or tri halo derivatives on one or more carbon atoms. For alkyl, a nonlimiting example would be xe2x80x94CH2CHF2, xe2x80x94CF3 etc.
In all alkyl groups or carbon chains where one or more carbon atoms are optionally replaced by heteroatoms: O, S or N, it shall be understood that if N is not substituted then it is NH, it shall also be understood that the heteroatoms may replace either terminal carbon atoms or internal carbon atoms within a branched or unbranched carbon chain. Such groups can be substituted as herein above described by groups such as oxo to result in defintions such as but not limited to: alkoxycarbonyl, acyl, amido and thioxo.
The compounds of the invention are only those which are contemplated to be xe2x80x98chemically stablexe2x80x99 as will be appreciated by those skilled in the art. For example, a compound which would have a xe2x80x98dangling valencyxe2x80x99, or a xe2x80x98carbanionxe2x80x99 are not compounds contemplated by the invention.
The invention includes pharmaceutically acceptable derivatives of compounds of formula (I). A xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d refers to any pharmaceutically acceptable salt or ester of a compound of this invention, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound of this invention, a pharmacologically active metabolite or pharmacologically active residue thereof. A pharmacologically active metabolite shall be understood to mean any compound of the formula(I) capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative compounds of the formula(I).
Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of this invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and Nxe2x80x94(C1-C4 alkyl)4+ salts.
In addition, the compounds of this invention include prodrugs of compounds of the formula (I). Prodrugs include those compounds that, upon simple chemical transformation, are modified to produce compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when a prodrug of this invention is administered to a patient, the prodrug may be transformed into a compound of formula (I), thereby imparting the desired pharmacological effect.
In accordance with the invention, there are provided methods of using the compounds of the formula (I). The compounds of the invention effectively block inflammatory cytokine production from cells. The inhibition of cytokine production is an attractive means for preventing and treating a variety of cytokine mediated diseases or conditions associated with excess cytokine production, e.g., diseases and pathological conditions involving inflammation. Thus, the compounds of the invention are useful for the treatment of such conditions. These encompass diseases including, but not limited to, rheumatoid arthritis, osteoarthritis, traumatic arthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn""s disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus erythematosus, glomerulonephritis, reperfusion injury, sepsis, bone resorption diseases including osteoporosis, chronic obstructive pulmonary disease, congestive heart failure, Alzheimer""s disease, atherosclerosis, toxic shock syndrome, asthma, contact dermatitis, percutaneous transluminal coronary angioplasty (PTCA) and insulin-dependent diabetes mellitus.
In addition, the compounds of the invention being inhibitors of cytokine production are expected to block inducible cyclooxygenase (COX-2) expression. COX-2 expression has been shown to be increased by cytokines and it is believed to be the isoform of cyclooxygenase responsible for inflammation (M. K. O""Banion et al., Proc. Natl. Acad. Sci. U.S.A, 1992, 89, 4888.) Accordingly, the present novel compounds would be expected to exhibit efficacy against those disorders currently treated with COX inhibitors such as the familiar NSAIDs. These disorders include acute and chronic pain as well as symptoms of inflammation and cardiovascular disease.
As discussed in the Background of the Invention, IL-8 plays a role in the influx of neutrophils into sites of inflammation or injury. Therefore, in a yet further aspect of the invention, the compounds of the invention may be useful in the treatment of diseases mediated predominantly by neutrophils such as stroke and myocardial infarction, alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion associated syndromes, and necrotizing entrerocolitis.
For therapeutic use, the compounds of the invention may be administered in any conventional dosage form in any conventional manner. Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermally, orally, topically or by inhalation. The preferred modes of administration are oral and intravenous.
The compounds of this invention may be administered alone or in combination with adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutic compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients. Advantageously, such combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies. Compounds of the invention may be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. Advantageously, the compounds may then be administered together in a single dosage form. In some embodiments, the pharmaceutical compositions comprising such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of a compound of formula (I) (w/w) or a combination thereof. The optimum percentage (w/w) of a compound of the invention may vary and is within the purview of those skilled in the art. Alternatively, the compounds may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regime.
As mentioned above, dosage forms of the compounds of this invention include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances. Preferred dosage forms include, tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Dosage levels and requirements are well-recognized in the art and may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 1-1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000 mg/day may be required. As the skilled artisan will appreciate, lower or higher doses may be required depending on particular factors. For instance, specific dosage and treatment regimens will depend on factors such as the patient""s general health profile, the severity and course of the patient""s disorder or disposition thereto, and the judgment of the treating physician.
In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustrating preferred embodiments of this invention, and are not to be construed as limiting the scope of the invention in any way.
The examples which follow are illustrative and, as recognized by one skilled in the art, particular reagents or conditions could be modified as needed for individual compounds without undue experimentation. Starting materials used in the scheme below are either commercially available or easily prepared from commercially available materials by those skilled in the art.
The invention additionally provides for methods of making the compounds of the formula (I). The compounds of the invention may be prepared by the general methods and examples presented below, and methods known to those of ordinary skill in the art. Further reference in this regard may be made to U.S. Pat. Nos. 6,319,921 and 6,358,945, U.S. application Ser. Nos. 09/714,539, 09/611,109, 09/698,442, 09/834,797 and 09/902,085, and U.S. provisional application No. 60/283,642. Each of the aforementioned are incorporated herein by reference in their entirety. In all schemes, xe2x80x9cGxe2x80x9d in the formulas shown below shall have the meaning of the cycloalkyl group: 
shown in the formula (I); and Ar in the definition of xe2x80x9cGxe2x80x9d in the formulas below shall have the meaning of the carbocyclic group: 
shown in the formula (I) of the invention described hereinabove.
The compounds of the invention may be prepared by Method A, B, C or D as illustrated in Scheme I. 
In Method A, a mixture of an amine of formula (Iia) and an arylisocyanate of formula (III) is dissolved in a non-protic, anhydrous solvent such as THF, ether, toluene, dioxane or ethyl acetate. The preferred solvent is THF. The mixture is stirred at between 0-45xc2x0 C., preferably at 25xc2x0 C., for 2-24 h, and the volatiles are removed. Purification of the residue by recrystallization from an appropriate solvent such as ethyl acetate/hexanes, ethyl acetate/MeOH, THF/petroleum ether, EtOH/water or by silica gel chromatography, using for example, hexanes and ethyl acetate as eluents, provides the product of formula (I) or precursors thereof.
In Method B, an amine of formula (IIa) is dissolved in a halogenated solvent, such as methylene chloride, chloroform or dichloroethane. The preferred solvent is methylene chloride. The mixture is diluted with aqueous alkali, such as sodium bicarbonate or potassium carbonate, cooled in an ice bath and phosgene is added. The mixture is vigorously stirred for 5-30 min, with 10 min being preferable. The organic layer is dried, with agents such as MgSO4 or Na2SO4, and the volatiles removed to provide the corresponding isocyanate. The isocyanate and arylamine IV are mixed in a non-protic, anhydrous solvent such as THF, ether, toluene, dioxane, methylene chloride or ethyl acetate. The preferred solvent is THF. The mixture is stirred at between 0-45xc2x0 C., preferably at 25xc2x0 C., for 2-24 h, and the volatiles are removed. Purification of the residue by recrystallization or by silica gel chromatography, as above, provides the product of formula (I) or precursors thereof.
The required isocyanate may also be prepared from the carboxylic acid Gxe2x80x94CO2H by reaction with a chloroformate, such as ethyl chloroformate, in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as THF at about 0xc2x0 C. The resulting mixed anhydride is treated with an aqueous solution of sodium azide. Heating a solution of the resulting acyl azide in a suitable solvent, such as toluene, at about reflux, results in a Curtius rearrangement, providing the isocyanate Gxe2x80x94Nxe2x95x90Cxe2x95x90O in situ. Preferably, the isocyanate may also be prepared by treatment of Gxe2x80x94CO2H with diphenyl phosphorazidate and a suitable base, such as triethylamine, in a suitable solvent, such as DME, to form the acyl azide, followed by heating to accomplish the Curtius rearrangement.
In Method C, an amine of formula (IIa) is dissolved in a suitable solvent such as a halogenated solvent which includes methylene chloride, chloroform or dichloroethane. The preferred solvent is methylene chloride. A suitable base such as triethylamine may be added, followed by an alkyl or aryl chloroformate, such as t-butyl chloroformate or phenyl chloroformate (shown). The mixture is stirred at between 0-85xc2x0 C., preferably at reflux temperature, for 2-24 h, and the volatiles are removed providing carbamate (V). The carbamate and arylamine IV are mixed in a non-protic, anhydrous solvent such as THF, ether, toluene, dioxane, methylene chloride or ethyl acetate. The preferred solvent is THF. The mixture is stirred at between 0-110xc2x0 C., preferably at reflux temperature, for 2-24 h, and the volatiles are removed. Purification of the residue as above provides the product of formula (I) or precursors thereof. This process can also be performed in the reverse sense as illustrated by Method D.
In Method D an arylamine of formula (IV) is dissolved in a suitable solvent such as a THF. A suitable alkyl or aryl chloroformate, such as t-butyl chloroformate or phenyl chloroformate (shown), is added. The mixture is stirred at between 0-85xc2x0 C., preferably at 0xc2x0 C., for 2-24 h, at which time the reaction is quenched with aqueous, saturated sodium bicarbonate. Extractions with a suitable solvent, such as ethyl acetate, provide carbamate Va upon concentration. The carbamate and amine IIa are mixed in a non-protic, anhydrous solvent such as THF, ether, toluene, dioxane, methylene chloride or ethyl acetate. The preferred solvent is THF. The mixture is stirred at between 0-110xc2x0 C., preferably at 0xc2x0 C., for 2-48 h, in a sealed tube. PS-trisamine and PS-isocynate resins are added, and the reaction mixture was shaken for 3 days. Filtration and concentration provides the product of formula (I) or precursors thereof.
Amine intermediates of formula (IIa) are either commercially available or can be made by methods known to those skilled in the art. Compounds of formula (I) with n=1 may be prepared by Method B, via the isocyanate as illustrated in Scheme II. An aldehyde bearing R1 (or R2) (VI) is treated with carbethoxymethylene triphenylphosphorane in a suitable solvent, such as THF, to provide the alpha, beta-unsaturated ester VII. Treatment with diazomethane in the presence of palladium (II) acetate in a suitable solvent, such as dichloromethane-ether, at about 0xc2x0 C. to room temperature provides the cyclopropane carboxylic acid ester VIII. The ester is hydrolyzed to the corresponding carboxylic acid IX. Optionally the hydrolysis may be carried out prior to the cyclopropanation step. The carboxylic acid may then be converted to the isocyanate (X) via a Curtius rearrangement and reacted with the desired intermediate IV as described above for Method B. 
Methods by which intermediates III and IV, (Scheme I) may be prepared are known in the art. Several procedures are described and exemplified in the above-referenced patent applications.